Novel use of a peptide class of compound for treating non neuropathic inflammatory pain

ABSTRACT

The present invention concerns the use of compounds of the Formula (I) for treating different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain in mammals. The pain to be treated may be e.g. chronic inflammatory pain, rheumatoid arthritis pain and/or secondary inflammatory osteoarthritic pain. The compounds show an antinociceptive profile and differ from classical analgesics like opioids and non-steroidal anti-inflammatory drugs (NSAIDS) and are useful as specific analgesics.

FIELD OF THE INVENTION

The present invention is directed to the novel use of a peptide class ofcompound for treating different types and symptoms of acute and chronicpain, especially non neurophathic inflammatory pain.

BACKGROUND OF THE INVENTION

Certain peptides are known to exhibit central nervous system (CNS)activity and are useful in the treatment of epilepsy and other CNSdisorders. These peptides which are described in the U.S. Pat. No.5,378,729 have the Formula (I):

wherein

-   -   R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,        aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower        alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower        alkyl, and R is unsubstituted or is substituted with at least        one electron withdrawing group or electron donating group;    -   R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl,        aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic,        lower cycloalkyl, lower cycloalkyl lower alkyl, each        unsubstituted or substituted with an electron donating group or        an electron withdrawing group; and    -   R₂ and R₃ are independently hydrogen, lower alkyl, lower        alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic,        heterocyclic lower alkyl, lower alkyl heterocyclic, lower        cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and        R3 may be unsubstituted or substituted with at least one        electron withdrawing group or electron donating group;    -   Z is O, S, S(O)₂, NR₄, PR₄ or a chemical bond;    -   Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower        alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower        alkyl, and Y may be unsubstituted or substituted with an        electron donating group or an electron withdrawing group,        provided that when Y is halo, Z is a chemical bond, or    -   ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅,        SNR₄R₇, NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,    -   R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl,        aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R₄,        R₅ and R₆ may be unsubstituted or substituted with an electron        withdrawing group or an electron donating group; and    -   R₇ is R₆ or COOR₈ or COR₈;    -   R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl        or alkyl group may be unsubstituted or substituted with an        electron withdrawing group or an electron donating group; and    -   n is 1-4; and    -   a is 1-3.

U.S. Pat. No. 5,773,475 also discloses additional compounds useful fortreating CNS disorders. These compounds areN-benzyl-2-amino-3-methoxy-propionamide having the Formula (II):

wherein

-   -   Ar is aryl which is unsubstituted or substituted with halo; R₃        is lower alkoxy; and R₁ is lower alkyl especially methyl.

The patents are hereby incorporated by reference. However neither ofthese patents describe the use of these compounds as specific analgesicsfor the treatment of acute and chronic pain, especially rheumaticinflammatory pain. Particularly the antinociceptive profile andproperties of this class of compounds are not disclosed.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to the novel use of acompound having Formula (I) and/or Formula (II) showing antinociceptiveproperties for treating different types and symptoms of acute andchronic pain, especially non neuropathic inflammatory pain.

Particularly the present invention concerns the use of said compounds ofFormulae (I) and/or (II) for the preparation of a pharmaceuticalcomposition for the treatment of different types and symptoms of acuteand chronic pain, especially non neuropathic inflammatory pain. Thisinclude chronic inflammatory pain e.g. rheumatoid arthritis pain and/orsecondary inflammatory osteoarthritic pain.

A compound according to the invention has the general Formula (I)

wherein

-   -   R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,        aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower        alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower        alkyl, and R is unsubstituted or is substituted with at least        one electron withdrawing group, or electron donating group;    -   R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl,        aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic,        lower cycloalkyl, lower cycloalkyl lower alkyl, each        unsubstituted or substituted with an electron donating group or        an electron withdrawing group;    -   and    -   R₂ and R₃ are independently hydrogen, lower alkyl, lower        alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic,        heterocyclic lower alkyl, lower alkyl heterocyclic, lower        cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and        R₃ may be unsubstituted or substituted with at least one        electron withdrawing group or electron donating group;    -   Z is O, S, S(O)₂, NR₄, PR₄ or a chemical bond;    -   Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower        alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower        alkyl, lower alkyl, and Y may be unsubstituted or substituted        with an electron donating group or an electron withdrawing        group, provided that when Y is halo, Z is a chemical bond, or    -   ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅,        SNR₄R₇, NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇.    -   R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl,        aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R₄,        R₅ and R₆ may be unsubstituted or substituted with an electron        withdrawing group or an electron donating group;    -   R₇ is independently R₆ or COOR₈ or COR₈;    -   R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl        or alkyl group may be unsubstituted or substituted with an        electron withdrawing group or an electron donating group; and    -   n is 1-4; and    -   a is 1-3.

Furthermore a compound according to the invention has the generalFormula (II)

wherein

-   -   Ar is aryl which is unsubstituted or substituted with halo; R₃        is lower alkoxy; and R₁ is lower alkyl, especially methyl.

The present invention is also directed to the preparation ofpharmaceutical compositions comprising a compound according to Formula(I) and/or Formula (II) useful for the treatment of rheumaticinflammatory pain.

DETAILED DESCRIPTION OF THE INVENTION

As indicated hereinabove, the compounds of Formula I are useful fortreating pain, particularly non neuropathic inflammatory pain. This typeof pain includes chronic inflammatory pain e.g. rheumatoid arthritispain and/or secondary inflammatory osteoarthritic pain. They show ananti-nociceptive effectiveness.

These compounds are described in U.S. Pat. No. 5,378,729, the contentsof which are incorporated by reference.

As defined herein, the “alkyl” groups when used alone or in combinationwith other groups, are lower alkyl containing from 1 to 6 carbon atomsand may be straight chain or branched. These groups include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl,and the like.

The “aryl lower alkyl” groups include, for example, benzyl, phenethyl,phenpropyl, phenisopropyl, phenbutyl, diphenylmethyl, 1,1-diphenylethyl,1,2-diphenylethyl, and the like.

The term “aryl”, when used alone or in combination, refers to anaromatic group which contains from 6 up to 18 ring carbon atoms and upto a total of 25 carbon atoms and includes the polynuclear aromatics.These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclicand are fused rings. A polynuclear aromatic compound as used herein, ismeant to encompass bicyclic and tricyclic fused aromatic ring systemscontaining from 10-18 ring carbon atoms and up to a total of 25 carbonatoms. The aryl group includes phenyl, and the polynuclear aromaticse.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. Thearyl group also includes groups like terrocyenyl. “Lower alkenyl” is analkenyl group containing from 2 to 6 carbon atoms and at least onedouble bond.

These groups may be straight chained or branched and may be in the Z orE form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl,2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl,(Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1,3or 2,4-pentadienyl, and the like.

The term lower “alkynyl” is an alkynyl group containing 2 to 6 carbonatoms and may be straight chained as well as branched. It includes suchgroups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl and the like.

The term lower “cycloalkyl” when used alone or in combination is acycloalkyl group containing from 3 to 18 ring carbon atoms and up to atotal of 25 carbon atoms. The cycloalkyl groups may be monocyclic,bicyclic, tricyclic, or polycyclic and the rings are fused. Thecycloalkyl may be completely saturated or partially saturated. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl,cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl,adamantyl, and the like. Cycloalkyl includes the cis or trans forms.Furthermore, the substituents may either be in endo or exo positions inthe bridged bicyclic systems.

The term “electron-withdrawing and-electron donating” refer to theability of a substituent to withdraw or donate electrons, respectively,relative to that of hydrogen if the hydrogen atom occupied the sameposition in the molecule. These terms are well understood by one skilledin the art and are discussed in Advanced Organic Chemistry, by J. March,John Wiley and Sons, New York, N.Y., pp.16-18 (1985) and the discussiontherein is incorporated herein by reference. Electron withdrawing groupsinclude halo, including bromo, fluoro, chloro, iodo and the like; nitro,carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl,quaternary ammonium, trifluoromethyl, aryl lower alkyanoyl, carbalkoxyand the like. Electron donating groups include such groups as hydroxy,lower alkoxy, including methoxy, ethoxy and the like; lower alkyl, suchas methyl, ethyl, and the like; amino, lower alkylamino, di(loweralkyl)amino, aryloxy such as phenoxy, mercapto, lower alkylthio, loweralkylmercapto, disulfide (lower alkyldithio) and the like. One ofordinary skill in the art will appreciate that some of the aforesaidsubstituents may be considered to be electron donating or electronwithdrawing under different chemical conditions. Moreover, the presentinvention contemplates any combination of substituents selected from theabove-identified groups.

The term “halo” includes fluoro, chloro, bromo, iodo and the like.

The term “acyl” includes lower alkanoyl.

As employed herein, the heterocyclic substituent contains at least onesulfur, nitrogen or oxygen ring atom, but also may include one orseveral of said atoms in the ring. The heterocyclic substituentscontemplated by the present invention include heteroaromatics andsaturated and partially saturated heterocyclic compounds. Theseheterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic andare fused rings. They may contain up to 18 ring atoms and up to a totalof 17 ring carbon atoms and a total of up to 25 carbon atoms. Theheterocyclics are also intended to include the so-calledbenzoheterocyclics. Representative heterocyclicx include furyl, thienyl,pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl,triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl,morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl,indolinyl, pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl,furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl,pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the N-oxidesof the nitrogen containing heterocycles, such as the nitric oxides ofpyridyl, pyrazinyl, and pyrimidinyl and the like. The preferredheterocyclic are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl,indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl, imidazolyl,pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a 5 or6-membered heterocyclic compound. The especially preferred heterocyclicis furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazihyl.The most preferred heterocyclics are furyl and pyridyl.

The preferred compounds are those wherein n is 1, but di, tri andtetrapeptides are also contemplated to be within the scope of theclaims.

The preferred values of R is aryl lower alkyl, especially benzylespecially those wherein the phenyl ring thereof is unsubstituted orsubstituted with electron donating groups or electron withdrawinggroups, such as halo (e.g., F).

The preferred R₁ is H-or lower alkyl. The most preferred R₁ group ismethyl.

The most preferred electron donating substituents and electronwithdrawing substituents are halo, nitro, alkanoyl, formyl,arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido, cyano,sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, loweralkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, loweralkyl, amino, lower alkylamino, di(loweralkyl) amino, amino lower alkyl,mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide”encompasses mercapto, mercapto alkyl and alkylthio, while the termdisulfide encompasses alkyidithio. These preferred substituents may besubstituted on any one of R₁, R₂, R₃, R₄, R₅ or R₆, R₇ or R₈ as definedherein.

The ZY groups representative of R₂ and R₃ include hydroxy, alkoxy, suchas methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such asthiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino;alkylamino, such as methylamino, ethylamino; arylamino, such as anilino;lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt,hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino,N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino,aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino(—NH—OH), lower alkoxy amino [(NHOR₁₈) wherein R₁₈ is lower alkyl],N-lower alkylhydroxyl amino [(NR₁₈)OH wherein R₁₈ is lower alkyl],N-lower alkyl-O-lower alkylhydroxyamino, i.e., [N(R₁₈)OR₁₉ wherein R₁₈and R₁₉ are independently lower alkyl], and o-hydroxylamino (—O—NH₂);alkylamido such as acetamido; trifluoroacetamido; lower alkoxyamino,(e.g., NH(OCH₃); and heterocyclicamino, such as pyrazoylamino.

The preferred heterocyclic groups representative of R₂ and R₃ aremonocyclic heterocyclic moieties the formula:

or those corresponding partially or fully saturated form thereof whereinn is 0 or 1; and

-   -   R₅₀ is H or an electron withdrawing group or electron donating        group;    -   A, Z L and J are independently CH, or a heteroatom selected from        the group consisting of N, O, S; and    -   G is CH, or a heteroatom selected from the group consisting of        N, O and S,    -   but when n is O, G is CH, or a heteroatom selected from the        group consisting of NH, O and S with the proviso that at most        two of A, E, L, J and G are heteroatoms.

When n is O, the above heteroaromatic moiety is a five membered ring,while if n is 1, the heterocyclic moiety is a six membered monocyclicheterocyclic moiety. The preferred heterocyclic moieties are thoseaforementioned heterocyclics which are monocyclic.

If the ring depicted hereinabove contains a nitrogen ring atom, then theN-oxide forms are also contemplated to be within the scope of theinvention.

When R₂ or R₃ is a heterocyclic of the above formula, it may be bondedto the main chain by a ring carbon atom. When n is O, R₂ or R₃ mayadditionally be bonded to the main chain by a nitrogen ring atom.

Other preferred moieties of R₂ and R₃ are hydrogen, aryl, e.g., phenyl,aryl alkyl, e.g., benzyl and alkyl.

It is to be understood that the preferred groups of R₂ and R₃ may beunsubstituted or substituted with electron donating or electronwithdrawing groups. It is preferred that R₂ and R₃ are independentlyhydrogen, lower alkyl, which is either unsubstituted or substituted withan electron withdrawing group or an electron donating group, such aslower alkoxy (e.g., methoxy, ethoxy, and the like), N-hydroxylamino,N-lower alkylhydroxyamino, N-loweralkyl-O-loweralkyl andalkylhydroxyamino.

It is even more preferred that one of R₂ and R₃ is hydrogen.

It is preferred that n is one.

It is preferred that R₂ is hydrogen and R₃ is hydrogen, an alkyl groupwhich is unsubstituted or substituted by at least an electron donatingor electron withdrawing group or ZY. In this preferred embodiment, it ismore preferred that R₃ is hydrogen, an alkyl group such as methyl, whichis unsubstituted or substituted by an electron donating group, or NR₄OR₅or ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen or loweralkyl. It is preferred that the electron donating group is lower alkoxy,and especially methoxy or ethoxy.

It is also preferred that R is aryl lower alkyl. The most preferred arylfor R is phenyl. The most preferred R group is benzyl. In a preferredembodiment, the aryl group may be unsubstituted or substituted with anelectron donating or electron withdrawing group. If the aryl ring in Ris substituted, it is most preferred that it is substituted with anelectron withdrawing group, especially on the aryl ring. The mostpreferred electron withdrawing group for R is halo, especially fluoro.

The preferred R, is loweralkyl, especially methyl.

The more preferred compounds are compounds of Formula (I) wherein n is1; R₂ is hydrogen; R₃ is hydrogen, an alkyl group, especially methylwhich is substituted by an electron donating or electron withdrawinggroup or ZY; R is aryl, aryl lower alkyl, such as benzyl, wherein thearyl group is unsubstituted or substituted and R₁ is lower alkyl. Inthis embodiment, it is most preferred that R₃ is hydrogen, an alkylgroup, especially methyl, substituted by electron donating group, suchas lower alkoxy, (e.g., methoxy, ethoxy and the like), NR₄OR₅ or ONR₄R₇wherein these groups are defined hereinabove.

The most preferred compounds utilized are those of the Formula (II):

wherein

-   -   Ar is aryl, especially phenyl, which is unsubstituted or        substituted with at least one electron donating group or        electron withdrawing group,    -   R₁ is lower alkyl; and    -   R₃ is as defined herein, but especially hydrogen, loweralkyl,        which is unsubstituted or substituted by at least an electron        donating group or electron withdrawing group or ZY. It is even        more preferred that R₃ is, in this embodiment, hydrogen, an        alkyl group which is unsubstituted or substituted by an electron        donating group, NR₄OR₅ or ONR₄R₇. It is most preferred that R₃        is CH₂-Q, wherein Q is lower alkoxy, NR₄OR₅ or ONR₄R₇ wherein R₄        is hydrogen or alkyl containing 1-3 carbon atoms, R₅ is hydrogen        or alkyl containing 1-3 carbon atoms, and R₇ is hydrogen or        alkyl containing 1-3 carbon atoms.

The preferred R₁ is CH₃. The most preferred R₃ is methoxy.

The most preferred aryl is phenyl.

The most preferred compound includes:

-   -   (R)-2-acetamido-N-benzyl-3-methoxy-propionamide,    -   O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;    -   O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;    -   N-acetyl-D-phenylglycine benzylamide;    -   D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid        benzylamide;    -   D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid        benzylamide.

It is to be understood that the various combinations and premutations ofthe Markush groups of R₁, R₂, R₃, R and n described herein arecontemplated to be within the scope of the present invention. Moreover,the present invention also encompasses compounds and compositions whichcontain one or more elements of each of the Markush groupings in R₁, R₂,R₃, n and R and the various combinations thereof. Thus, for example, thepresent invention contemplates that RI may be one or more of thesubstituents listed hereinabove in combination with any and all of thesubstituents of R₂, R₃, and R with respect to each value of n.

The compounds utilized in the present invention may contain one (1) ormore asymmetric carbons and may exist in racemic and optically activeforms. The configuration around each asymmetric carbon can be either theD or L form. It is well known in the art that the configuration around achiral carbon atoms can also be described as R or S in theCahn-Prelog-Ingold nomenclature system. All of the variousconfigurations around each asymmetric carbon, including the variousenantiorriers and diastereomers as well as racemic mixtures and mixturesof enantiomers, diastereomers or both are contemplated by the presentinvention.

In the principal chain, there exists asymmetry at the carbon atom towhich the groups R₂ and R₃ are attached. When n is 1, the compounds ofthe present invention is of the formula

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, Z and Y are as defined previously.

As used herein, the term configuration shall refer to the configurationaround the carbon atom to which R₂ and R₃ are attached, even thoughother chiral centers may be present in the molecule. Therefore, whenreferring to a particular configuration, such as D or L, it is to beunderstood to mean the D or L stereoisomer at the carbon atom to whichR₂ and R₃ are attached. However, it also includes all possibleenantiomers and diastereomers at other chiral centers, if any, presentin the compound.

The compounds of the present invention are directed to all the opticalisomers, i.e., the compounds of the present invention are either theL-stereoisomer or the D-stereoisomer (at the carbon atom to which R₂ andR₃ are attached). These stereoisomers may be found in mixtures of the Land D stereoisomer, e.g., racemic mixtures. The D stereoisomer ispreferred.

Depending upon the substituents, the present compounds may form additionsalts as well. All of these forms are contemplated to be within thescope of this invention including mixtures of the stereoisomeric forms

The preparation of the utilized compounds are described in U.S. Pat.Nos. 5,378,729 and 5,773.475, the contents of both of which areincorporated by reference.

The compounds utilized in the present invention are useful as such asdepicted in the Formula I or can-be employed in the form of salts inview of its basic nature by the presence of the free amino group. Thus,the compounds of Formula I forms salts with a wide variety of acids,inorganic and organic, including pharmaceutically acceptable acids. Thesalts with therapeutically acceptable acids are of course useful in thepreparation of formulation where enhanced water solubility is mostadvantageous.

These pharmaceutically acceptable salts have also therapeutic efficacy.These salts include salts of inorganic acids such as hydrochloric,hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid andsulfuric acids as well as salts of organic acids, such as tartaric,acetic, citric, malic, benzoic, perchloric, glycolic, gluconic,succinic, aryl sulfonic, e.g., p-toluene sulfonic acids,benzenesulfonic), phosphoric, malonic, and the like.

It is preferred that the compound utilized in the present invention isused in therapeutically effective amounts.

The physician will determine the dosage of the present therapeuticagents which will be most suitable and it will vary with the form ofadministration and the particular compound chosen, and furthermore, itwill vary with the patient under treatment, the age of the patient, thetype of malady being treated. He will generally wish to initiatetreatment with small dosages substantially less than the optimum dose ofthe compound and increase the dosage by small increments until theoptimum effect under the circumstances is reached. It will generally tofound that when the composition is administered orally, largerquantities of the active agent will be required to produce the sameeffect as a smaller quantity given parenterally. The compounds areuseful in the same manner as comparable therapeutic agents and thedosage level is of the same order of magnitude as is generally employedwith these other therapeutic agents.

In a preferred embodiment, the compounds utilized are administered inamounts ranging from about 1 mg to about 100 mg per kilogram of bodyweight per day. This dosage regimen may be adjusted by the physician toprovide the optimum therapeutic response. For example, several divideddoses may be administered daily or the dose may be proportionallyreduced as indicated by the exigencies of the therapeutic situation. Thecompounds of Formula I may be administered in a convenient manner, suchas by oral, intravenous (where water soluble), intramuscular orsubcutaneous routes.

The compounds of Formula (I) may be orally administered, for example,with an inert diluent or with an assimilable edible carrier, or it maybe enclosed in hard or soft shell gelatin capsules, or it may becompressed into tablets, or it may be incorporated directly into thefool of the diet. For oral therapeutic administration, the activecompound of Formula I may be incorporated with excipients and used inthe form of ingestible tablets, buccal tablets, troches, capsules,elixirs, suspensions, syrups, wafers, and the like. Such compositionsand preparations should contain at least 1% of active compound ofFormula I. The percentage of the compositions and preparations may, ofcourse, be varied and may conveniently be between about 5 to about 80%of the weight of the unit. The amount of active compound of Formula I insuch therapeutically useful compositions is such that a suitable dosagewill be obtained. Preferred compositions or preparations according tothe present invention contains between about 10 mg and 6 g activecompound of Formula I.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier.

Various other materials may be present as coatings or otherwise modifythe physical form of the dosage unit. For instance, tablets, pills, orcapsules may be coated with shellac, sugar or both. A syrup or elixirmay contain the active compound, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and flavoring such as cherryor orange flavor. Of course, any material used in preparing any dosageunit form should be pharmaceutically pure and substantially non-toxic inthe amounts employed. In addition, the active compound may beincorporated into sustained-release preparations and formulations. Forexample, sustained release dosage forms are contemplated wherein theactive ingredient is bound to an ion exchange resin which, optionally,can be coated with a diffusion barrier coating to modify the releaseproperties of the resin.

The active compound may also be administered parenterally orintraperitoneally. Dispersions can also be prepared in glycerol, liquid,polyethylene glycols, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases the form must be sterile and mustbe fluid to the extent that easy syringability exists. It must be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminiummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying the freeze-dryingtechnique plus any additional desired ingredient from previouslysterile-filtered solution thereof.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagent, isotonic and absorption delaying agents for pharmaceutical activesubstances as well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active ingredient, its use inthe therapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form or ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specifics for the novel dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the active material an the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such as active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form as hereinbeforedescribed. A unit dosage form can, for example, contain the principalactive compound in amounts ranging from about 10 mg to about 6 g.Expressed in proportions, the active compound is generally present infrom about 1 to about 750 mg/ml of carrier. In the case of compositionscontaining supplementary active ingredients, the dosages are determinedby reference to the usual dose and manner of administration of the saidingredients.

As used herein the term “patient” or “subject” refers to a warm bloodedanimal, and preferably mammals, such as, for example, cats, dogs,horses, cows, pigs, mice, rats and primates, including humans. Thepreferred patient is humans.

The term “treat” refers to either relieving the pain associated with adisease or condition or alleviating the patient's disease or condition.

The compounds of the present invention are useful for treating chronicpain. As used herein, the term “chronic pain” is defined as painpersisting for an extended period of time, for example, greater thanthree to six months, although the characteristic signs describedhereinbelow can occur earlier or later than this period. Vegetativesigns, such as lassitude, sleep disturbances, decreased appetite, loseof taste or food, weight loss, diminished libido and constipationdevelop.

Types of pain that the compounds of the present invention are especiallyuseful in treating are is acute and chronic pain, particularly nonneuropathic inflammatory pain. This include chronic inflammatory pain,e.g. rheumatoid arthritis pain and/or secondary inflammatoryosteoarthritic pain.

The compounds of the present invention are administered to a patientsuffering from the aforementioned type of pain in an analgesic effectiveamount. These amounts are equivalent to the therapeutically effectiveamounts described hereinabove.

The following working examples show the antinoiceptive properties inwell-defined animal models of acute and chronic pain.

The used substance was SPM 927 which is the synonym for Harkoseride. Thestandard chemical nomenclature is(R)-2-acetamide-N-benzyl-3-methoxypropionamide.

1. EXAMPLE 1

Formalin Test, Rat

Prolonged Unflammatory Pain

Significant and dose dependent efficacy of SPM 927 could be demonstratedin the late phase of the rat formalin test.

The formalin test is a chemically-induced tonic pain model in whichbiphasic changes of nociceptive behaviour are assessed andspinal/supraspinal plasticity of nociception is considered as amolecular basis for neuropathic pain particularly during the second(=late) phase of the test, during which most clinically used drugsagainst neuropathic pain are active. These features have resulted in theformalin test being accepted as a valid model of persistent clinicalpain.

The compound was tested for anti-nociceptive properties by use of theweighted behavioural scoring method: Freely moving animals underwentobservational assessment of the position of the left hind paw accordingto a rating score scaled 0-3 before and 10, 20, 30 and 40 min afterinjection of 0.05 ml of sterile 2.5% formalin under the skin on thedorsal surface of the paw. SPM 927, administered i.p. just prior toformalin injection produced dose dependant reduction of theformalin-induced tonic inflammatory nociceptive behaviour as shown intable 1 (weighted pain scores±SEM, n=11-12/group). TABLE 1 Weighted painscore, formalin test, rat Time After Injection of formalin Dose No. ofand SPM 927 [mg/kg] Animals BASELINE 10 MIN 20 MIN 30 MIN 40 MIN 0 110.00 ± 0.00 0.30 ± 0.16 0.93 ± 0.21 1.84 ± 0.19 2.10 ± 0.24 5 12 0.01 ±0.01 0.31 ± 0.11 0.78 ± 0.23 1.47 ± 0.20 1.46 ± 0.19* 10 11 0.00 ± 0.000.42 ± 0.17 0.33 ± 0.16* 1.02 ± 0.27* 1.05 ± 0.19* 20 12 0.00 ± 0.000.48 ± 0.18 0.57 ± 0.14 0.78 ± 0.18* 1.02 ± 0.24* 40 12 0.00 ± 0.00 0.12± 0.05 0.10 ± 0.04* 0.09 ± 0.06* 0.12 ± 0.06**= Significant difference from vehicle (ANOVA corrected for multiplecomparisons p ≦ 0.05.

The term ANOVA stands for Analysis of Variance.

2. EXAMPLE 2

Chronic Constriction Injury (CCI, Benneff-Model)

The effectiveness of SPM 927 in reducing spontaneous chronic pain,mechanical allodynia, and thermal hyperalgesia was tested using thechronic constriction injury (CCI) model of peripheral neuropathy, one ofthe best characterised in vivo animal models used to study chronic paindue to peripheral nerve injury. In this model, loose ligatures areplaced around the sciatic nerve, which produces axonal swelling and apartial deafferentation manifested as a significant but incomplete lossof axons in the distal portion of the peripheral nerve. One of theprominent behaviours seen following sciatic nerve ligation is theappearance of hind paw guarding, thought to be an indication of anongoing spontaneous chronic pain. Support for this idea is derived fromreports of increased spinal cord neural activity, and increasedspontaneous neurohal discharge in spinothalamic tract neurons and in theventrobasal thalamus in the absence of overt peripheral stimulation. Inaddition to the appearance of spontaneous pain behaviours, severalabnormalities in stimulus evoked pain occur as a result of CCI,including thermal hyperalgesia and mechanical allodynia. The developmentof these abnormal stimulus-evoked pains has also been reported asoccurring in areas outside the territory of the damaged nerve, areasinnervated by uninjured nerves.

Behavioural tests for thermal hyperalgesia, and mechanical allodyniawere conducted to evaluate different components of neuropathic pain.Baseline data for each test was collected prior to any experimentalprocedure; in addition, all animals were tested for the development ofchronic pain behaviours 13-25 days after CCI surgery 1 day prior to theday of vehicle: (0.04 ml sterile water/10 g body weight) or drugadministration and after vehicle/drug administration. The sequence ofthe tests was pain-related behaviour (1) thermal hyperalgesia, (2)mechanical allodynia in order to minimise the influence of one test onthe result of the next. The testing procedures and results are presentedseparately for each aspect of chronic pain. Either 0 (vehicle, 0.04ml/10 g body weight), 5, 10, 20 or 40 mg/kg of SPM 927 (n=7-23/group)was administered i.p. 15 minutes before the first behavioural test.

(1) Thermal hyperalgesia was assessed by means of withdrawal latency inresponse to radiant heat applied to the subplantar surface of theligated rat hind paw according to Hargreaves. As compared to thebaseline latency (s), a significant decrease in the (postoperative)latency of foot withdrawal in response to the thermal stimulus wasinterpreted as indicating the presence of thermal hyperalgesia followingchronic constriction injury.

SPM 927 dose dependently reduced chronic constriction injury-inducedthermal hyperalgesia as shown in table 2 [latencies (s)±SEM].Significant effects were observed only at the highest doses tested (20and 40 mg/kg i.p.) with the maximum effect seen already at 20 mg/kg i.p.TABLE 2 Thermal hyperalgesia, CCI model, rat Post- Dose No. of Post-operative + SPM [mg/kg] Animals Baseline operative 927 0 13  9.7 ± 0.736.9 ± 0.28  7.3 ± 0.42 5 7 10.5 ± 0.68 8.1 ± 0.59  9.1 ± 0.97 10 7  9.2± 0.68 7.0 ± 0.60  8.0 ± 0.58 20 8  9.9 ± 0.69 6.9 ± 0.56  9.7 ± 0.95*40 8  8.3 ± 0.57 7.4 ± 0.47 10.2 ± 0.77**= Significant difference from vehicle (ANOVA corrected for multiplecomparisons p ≦ 0.05.

Mechanical sensitivity and allodynia of the ligated rat hind paw wasquantified by brisk foot withdrawal in response to normally innocuousmechanical stimuli as described previously. Responsiveness to mechanicalstimuli was tested with a calibrated electronic Von Frey pressurealgometer connected to an online computerised data collection system. Asignificant decrease in the post operative compared to baseline pressure(g/mm²) necessary to elicit a brisk foot withdrawal in response to thismechanical stimulus is interpreted as mechanical allodynia.

(2) SPM 927 dose dependently reduced the intensity of mechanicalallodynia induced by unilateral nerve ligation as shown in table 3[pressure (g/mM²)±SEM]. Regression analysis showed a positive linearcorrelation between the dose of SPM 927 and the increase in the amountof force required to produce foot withdrawal. TABLE 3 Mechanicalallodynia, CCI model, rat Post- Dose No. of Post- operative + SPM[mg/kg] Animals Baseline operative 927 0 20 41.6 ± 2.20 18.7 ± 2.08 20.2± 1.89 5 11 53.6 ± 3.34 16.4 ± 2.56 21.8 ± 2.33 10 17 42.9 ± 2.54 21.1 ±2.12 29.2 ± 2.84* 20 8 46.0 ± 2.62 24.6 ± 2.78 39.5 ± 3.62* 40 9 48.3 ±3.83 23.8 ± 2.23 42.9 ± 5.47**= Significant difference from vehicle (ANOVA corrected for multiplecomparisons, p ≦ 0.05).

3. EXAMPLE 3

Randall-Selitto Paw Pressure Test, Rat

Further potential anti-nociceptive efficacy of SPM 927 was assessed in arat experimental model of acute inflammation using a modified Randalland Selitto. procedure. Acute inflammation is induced by injection ofs.c. carrageenen (1.0 mg in 0.1 ml saline/paw), an unspecificinflammatory agent, into the plantar surface of one hind paw of theanimal. Mechanical sensitivity and nociceptive thresholds were measuredusing an algesimeter device that exerts a constantly increasingmechanical force (10 mm Hg/sec) on the inflamed hind paw. The mechanicalnociceptive threshold is defined as the pressure (mm Hg) at which therat vocalises or struggles or withdraws its paw. Since its originaldescription, the Randall and Selitto mechanical paw pressure test hasbecome a standard method for testing the-efficacy of new compounds foralleviating acute inflammatory pain.

SPM 927 or vehicle (sterile water, 0.04 ml/10 g body weight) wasadministered i.p 1 hr and 45 minutes after carrageenen, meaning 15 to 20minutes before the start of behavioural testing. As compared to theresponse threshold of vehicle-treated controls, an increase in thepressure required to produce a behavioural response is interpreted asantinociception. SPM 927 at 20 and 40 mg/kg i.p. significantly increasedthe pressure required to elicit a paw withdrawal during acutecarrageenen induced inflammation in the Randall-Selitto paw pressuretest, indicating a reduction of mechanical hyeralgesia as shown in table4 [pressure (mm Hg)±SEM, n=12/group]. TABLE 4 Mechanical hyperalgesia,modified Randall-Selitto, rat Dose Carrageenen + SPM [mg/kg] BaselineCarrageenen alone 927 0 101.5238 ± 14,9666 40.85714 ± 9,319 45.07143 ±5,569 20 142.5694 ± 12.834  108.222 ± 10.180 164.7639 ± 13.533* 40164.8889 ± 18.360  89.963 ± 7.457  232.741 ± 22.034**= Significant difference from vehicle (ANOVA corrected for multiplecomparisons, p ≦ 0.05).

Due to high variation of baseline responses and mechanical hyperalgesiafollowing carrageenen injection, a direct comparison of the absolute pawpressures required to elicit a behavioural response is inappropriate.However, vehicle (0 mg/kg, sterile water, 0.04 ml/10 g body weight) hadlittle effect on behavioural responsiveness, but SPM 927 at doses of 20and 40 mg/kg i.p. markedly reduced the mechanical hyperalgesia inducedby carrageenen.

Test Results

Harkoseride proved to be anti-nociceptive in several differentexperimental animal models that reflect different types and symptoms ofpain. The prolonged inflammatory nociception produced in the ratformalin test and mechanical allodynia in the rat CCI model appearedmost sensitive to the effects of SPM 927, showing significant dosedependent reductions in nociceptive behaviour measurements, even at the10 mg/kg i.p. dose. In addition, but at higher doses SPM 927 exhibitedstatistically significant reduction in pain on other types ofnociception, thermal hyperalgesia (paw flick Hargreaves test, rat CCImodel), and mechanical hyperalgesia due to acute inflammation (modifiedrat Randall-Selitto test).

Thus, the anti-nociceptive profile of SPM 927 differs from classicalanalgesics like opioids and the standard anti-inflammatory drugs of theNSAID-type (non-steroidal anti-inflammatory drug), furthermore andsurprisingly, the antinociceptive profiling obtained and described bythe data given table 1-4 is even different to other anticonvulsant drugsused for pain relief.

The weak but not significant effects on thermal and mechanicalhyperalgesia led to the following investigation:

4. EXAMPLE 4

Antinociceptive Effects of Harkoseride in an Animal Model for RheumatoidArthritis

In the following study harkoseride is hereinafter referred to as SPM927.

Method:

Experiments were performed in female Wistar rats weighing 80-90 g at thebeginning of the experiments. Arthritis was induced by intraplantarinjection of Freund's complete adjuvans (FCA, 0.1 ml) to one hindpaw.Drugs were given on day 11 after FCA injection in animals whichdeveloped systemic secondary arthritic symptoms as assessed by visualinspection. Mechanical hyperalgesia was than acutely applied andmeasured by means of the paw pressure test (Randall Selitto method) andsupraspinal vocalization as the biological endpoint of the nociceptivereaction. Measurements were taken at 0 min (before drug injection) and15 min, 30 min, 60 min, and 24 h after drug injection and all data areexpressed as percent of maximal possible effect (% MPE).

10 groups of 15 rats were used and received the following treatments:drug No. FCA [dose in mg/kg]/time comment 1 no no healthy controls 2 yesno arthritic controls 3 yes SPM 927 [5] acute treatment group(anti-nociceptive effects) 4 yes SPM 927 [10] acute treatment group(anti-nociceptive effects) 5 yes SPM 927 [20] acute treatment group(anti-nociceptive effects) 6 yes SPM 927 [30] acute treatment group(anti-nociceptive effects) 7 yes SPM 927 [40] acute treatment group(anti-nociceptive effects) 8 yes SPM 927 [30] early treatment group(anti-inflammatory (with FCA) effects) 9 no morphine [10] positivecontrol group (normal condition) 10 yes morphine [10] positive controlgroup (disease condition)

Results: % MPE group # treatment 15 min 30 min 60 min 24 h 1 Control −5−2 +2 −5 2 FCA/VEH +12 +2 0 +3 3 FCA/SPM 5 −5 −5 −12 −14 4 FCA/SPM 10 +7−2 0 −5 5 FCA/SPM 20 +1 −20 −9 −20 6 FCA/SPM 30 +58 +33 +16 −8 7 FCA/SPM40 +100 +100 +14 −7 8 FCA/SPM 30 −14 −7 −3 −11 (early) 9 MOR 10 +100+100 +100 +2 10 FCA/MOR10 +100 +100 +100 −7

SPM 927 showed dose-dependent anti-nociceptive but no anti-inflammatoryeffects. The anti-nociceptive effects started at a dose of 30 mg/kg andwere most prominent during the first 30 min of testing. Morphine, as apositive control substance had clear antinociceptive effects inarthritic and normal animals.

Conclusion:

Surprisingly and unexpected SPM 927 shows dose-dependent antinociceptiveeffects in rats that suffer from Freund's complete adjuvans inducedarthritis (significant so at doses of 30 and 40 mg/kg). Thisantinociception is not caused by potential anti-inflammatory effects.Under this chronic inflammatory pain condition the antinociceptiveeffect of SPM 927 (see FIG. 1) showed full intrinsic activity and,suggests SPM 927 to be effective in rheumatoid arthritic pain as well assecondary inflammatory osteoarthritis.

1-35. (canceled)
 36. A method of treating a mammal suffering from orsusceptible to acute or chronic pain, comprising administering to themammal an effective amount of a compound of the following Formula (I):

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or electron donating group; R₁ is hydrogen or lower alkyl, loweralkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic loweralkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl,each unsubstituted or substituted with an electron donating group or anelectron withdrawing group; R₂ and R₃ are independently hydrogen, loweralkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, halo,heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and R₃ maybe unsubstituted or substituted with at least one electron withdrawinggroup or electron donating group; and wherein heterocyclic in R₂ and R₃is furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl,oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl,quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl,morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl,indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl,furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl,pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl; Z is O, S, S(O)₂,NR₆′; or PR₄; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, loweralkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Ymay be unsubstituted or substituted with an electron donating group oran electron withdrawing group, or ZY taken together is NR₄NR₅R₇, NR₄OR₅,ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇, NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆ orPR₄NR₅R₇,

R₆′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and R₄ maybe unsubstituted or substituted with an electron withdrawing group orelectron donating group; R₄, R₅ and R₆ are independently hydrogen, loweralkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, whereinR₄, R₅ and R₆ may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; and R₇, is COOR₈, COR₈,hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or loweralkynyl, which R₇ may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; R₈ is hydrogen or loweralkyl, or aryl lower alkyl, and the aryl or alkyl group may beunsubstituted or substituted with an electron withdrawing group or anelectron donating group; and n is 1-4; wherein each electron-withdrawinggroup is bromo, fluoro, chloro, iodo, nitro, carboxy, lower alkenyl,lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium,trifluoromethyl, aryl lower alkanoyl, or carbalkoxy; wherein eachelectron-donating group is hydroxy, lower alkoxy, lower alkyl, amino,lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, loweralkylthio, lower alkylmercapto, or disulfide (lower alkyldithio); or apharmaceutically acceptable salt thereof.
 37. The method of claim 36wherein R is substituted with at least one electron-withdrawing group.38. The method of claim 36 wherein R is substituted with at least oneelectron-donating group.
 39. The method of claim 36 wherein R₂ and R₃are each independently monocyclic heterocyclic moieties of formula:

where R₅₀ is H, an electron-donating group or an electron-withdrawinggroup; A, E, L. and J are independently CH, or a heteroatom selectedfrom the group consisting of N, O, S; n is 0 or 1; and G is CH or aheteroatom selected from the group consisting of N, O, S.
 40. The methodof claim 36, wherein n is 1, R₂ is H, R₃ is hydrogen, an alkyl groupwhich is substituted by an electron withdrawing group or an electrondonating group or ZY, R is aryl, aryl lower alkyl, wherein the arylgroup is substituted or unsubstituted, and R₁ is lower alkyl.
 41. Themethod of claim 36, wherein the effective amount is between about 1 mgto about 100 mg per kilogram of body weight per day.
 42. The method ofclaim 36, wherein the compound is administered orally.
 43. The method ofclaim 36, wherein the compound is administered intravenously.
 44. Themethod of claim 36, wherein the compound is administered muscularly 45.The method of claim 36, wherein the compound is administeredsubcutaneously.
 46. The method of claim 36, wherein the compound is theL-stereoisomer.
 47. The method of claim 36, wherein the compound is theD-stereoisomer.
 48. A method of treating a mammal suffering from orsusceptible to acute or chronic pain, comprising administering to themammal an effective amount of a composition comprising a compound of thefollowing Formula (I):

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or electron donating group; R₁ is hydrogen or lower alkyl, loweralkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic loweralkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl,each unsubstituted or substituted with an electron donating group or anelectron withdrawing group; R₂ and R₃ are independently hydrogen, loweralkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, halo,heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and R₃ maybe unsubstituted or substituted with at least one electron withdrawinggroup or electron donating group; and wherein heterocyclic in R₂ and R₃is furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl,oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl,quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl,morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl,indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl,furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl,pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl; Z is O, S, S(O)₂,NR₆′; or PR₄; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, loweralkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Ymay be unsubstituted or substituted with an electron donating group oran electron withdrawing group, or ZY taken together is NR₄NR₅R₇, NR₄OR₅,ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇, NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆ orPR₄NR₅R₇,

R₆′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and R₄ maybe unsubstituted or substituted with an electron withdrawing group orelectron donating group; R₄, R₅ and R₆ are independently hydrogen, loweralkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, whereinR₄, R₅ and R₆ may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; and R₇, is COOR₈, COR₈,hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or loweralkynyl, which R₇ may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; and R₈ is hydrogen orlower alkyl, or aryl lower alkyl, and the aryl or alkyl group may beunsubstituted or substituted with an electron withdrawing group or anelectron donating group; and n is 1-4; or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.
 49. The methodof claim 48 wherein the composition further comprises a supplementaryactive ingredient.
 50. The method of claim 48 wherein the activecompound is present in from about 1 to about 750 mg/mL of carrier. 51.The method of claim 48 wherein R₂ and R₃ are each independentlymonocyclic heterocyclic moieties of formula:

where R₅₀ is H, an electron-donating group or an electron-withdrawinggroup; A, E, L. and J are independently CH, or a heteroatom selectedfrom the group consisting of N, O, S; n is 0 or 1; and G is CH or aheteroatom selected from the group consisting of N, O, S.
 52. The methodof claim 48, wherein n is 1, R₂ is H, R₃ is hydrogen, an alkyl groupwhich is substituted by an electron withdrawing group or an electrondonating group or ZY, R is aryl, aryl lower alkyl, wherein the arylgroup is substituted or unsubstituted, and R, is lower alkyl.
 53. Themethod of claim 48 wherein the compound is:(R)-2-acetamide-N-benzyl-3-methoxy-propionamide;O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;N-acetyl-D-phenylglycinebenzylamide; D-1,2=(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; orD-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide; or apharmaceutically acceptable salt thereof.